Synthesis of heteroarylamine intermediate compounds

ABSTRACT

Disclosed are novel 2-(5-halopyridyl) and 2-(5-halopyrimidinyl) magnesium halides, processes of making and their use in the efficient synthesis in their respective 5-halo-2-substituted pyridines and pyrimidines.

APPLICATION DATA

This application is a divisional of U.S. application Ser. No. 09/735,160 filed Dec. 12, 2000, which claims benefit of Prov. No. 60/206,327 filed May 23, 2000.

FIELD OF INVENTION

The present invention relates to synthesis of heteroarylamine intermediate compounds.

BACKGROUND OF THE INVENTION

Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production. These inhibitors are described as effective therapeutics in cytokine-mediated diseases, including inflammatory and autoimmune diseases. Examples of such compounds are reported in WO 99/23091 and in WO 98/52558.

A key step in the synthesis of these compounds is the formation of the urea bond. Various methods have been reported to accomplish this. For example, as reported in the above references, an aromatic or heteroaromatic amine, II, may be reacted with an aromatic or heteroaromatic isocyanate III to generate the urea IV (Scheme I)

If not commercially available, one may prepare the isocyanate III by reaction of an aryl or heteroaryl amine Ar₂NH₂ with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937) or trichloromethyl chlorofonmate (diphosgene) (K. Kurita, T. Matsumura and Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanate III, followed by reaction with Ar₁NH₂ to provide the urea. Other approaches to forming the urea reported in the chemical literature include reaction of a carbamate with an aryl or heteroaryl amine, (see for example B. Thavonekham, Synthesis, 1997, 1189 and T. Patonay et al., Synthetic Communications, 1996, 26, 4253) as shown in Scheme II below for a phenyl carbamate. U.S. patent application Ser. No. 09/611,109 also discloses a process of making heteroaryl ureas by reacting particular carbamate intermediates with the desired arylamine.

U.S. application Ser. No. 09/505,582 and PCT/US00/03865 describe cytokine inhibiting ureas of formula (I).

An Ar₂NH₂ required to prepare preferred compounds described therein is illustrated as formula (A).

wherein W, Y, and Z are described below.

The synthesis of II, a preferred formula (A) intermediate was described in U.S. application Ser. No. 09/505,582 and PCT/US00/03865 and is illustrated in Scheme III.

The synthesis begins with a palladium catalyzed carbonylation of 2,5-dibromopyridine (III) to provide ester IV in 55% yield. The reaction is run under pressure (80 psi CO) and must be monitored to minimize formation of the diester, an unwanted by-product. Reduction of IV with diisobutylaluminum hydride at −78° C. provides aldehyde V. This is followed by reductive amination to give VI.

Intermediate VI is then converted to II by reaction with t-BuLi at −78° C. followed by tributyltin chloride to give tributylstannane VII, followed by palladium catalyzed Stille coupling with intermediate VIII to give II. Conversion of VI and analogous intermediates to other intermediates of formula II via Suzuki coupling is also described in U.S. application Ser. No. 09/505,582 and PCT/US00/03865 (Scheme IV). According to this method, intermediate IX is treated with n-BuLi followed by trimethylborate to give arylboronic acid X. Palladium catalyzed Suzuki coupling with VI provides XI, which is deprotected by treatment with acid to give II.

This process is not well-suited for large-scale and commercial use for several reasons. One reaction (Scheme III) is run under high pressure (80 psi) and another at extreme temperature (−78° C.). The yield of IV is only moderate and by-product formation requires a purification step. These factors, plus the cost of starting materials and reagents make this process too costly for commercial scale.

The preparation of 2-bromo-5-lithiopyridine via reaction of 2,5-dibromopyridine with n-BuLi at −100° C. has been described (W. E. Parham and R. M. Piccirilli, J. Org. Chem., 1977, 42, 257). The selective formation of 2-bromo-5-pyridinemagnesium chloride via reaction with 2,5-dibromopyridine with i-PrMgCl at 0° C.-rt has also been reported (F. Trecourt et al., Tetrahedron Lett., 1999, 40, 4339). In these cases, the metal-halogen exchange occurred exclusively at the 5 position of the pyridine ring. However, the syntheses of 5-bromo-2-pyridinemagnesium chloride and 5-chloro-2-pyridinemagnesium chloride have not been reported previously.

The preparation of a lithium intermediate 5-chloro-2-lithiopyridine from 2-bromo-5-chloropyridine, has been reported (U. Lehmann et al., Chem., Euro. J., 1999, 5, 854). However, this synthesis requires reaction with n-BuLi at −78° C. The preparation of the 5-bromo-2-lithiopyridine from 2,5-dibromopyridine was reported by X. Wang et al. (Tetrahedron Letters, 2000, 4335). However, the method requires cryogenic and high dilution conditions. The selectivity was also dependent on reaction time. It is not suitable for large scale synthesis.

The synthesis of the intermediate 5-bromo-2-iodopyridine by refluxing 2,5-dibromopyridine in HI has been reported (U. Lehmann, ibid). A process using milder conditions for preparing 2-iodopyridine from 2-chloro or 2-bromopyridine has been described (R. C. Corcoran and S. H. Bang, Tetrahedon Lett., 1990, 31, 6757).

SUMMARY OF THE INVENTION

It is an object of the invention to provide novel 2-(5-halopyridyl) and 2-(5-halopyrimidinyl) magnesium halides, novel methods of producing them, and to provide a novel method of using said halides in the efficient synthesis of their respective 5-halo-2-substituted pyridines and pyrimidines.

It also an object of the invention to provide a novel method of producing heteroaryl amines of the formula (A)

wherein Ar, W, Y and Z are described below, the heteroaryl amines are useful in the production of heteroaryl ureas as mentioned above.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to a novel strategy for the synthesis of heteroarylamine compounds of the formula (A) which constitute the key component of pharmaceutically active compounds possessing a heteroaryl urea group.

The invention therefore provides for processes of making a compound of the formula (A)

wherein:

W is CR₃ or N, wherein R₃ is chosen from hydrogen, C₁₋₅alkyl, C₁₋₅alkoxy, arylC₀₋₅alkyl and —COR₄ wherein R₄ is chosen from C₁₋₅alkyl, C₁₋₅alkoxy, arylC₀₋₅alkyl and amino which is optionally independently di-substituted by C₁₋₅alkyl, and arylC₀₋₅alkyl; W is preferably CH or N,

Ar is chosen from

phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl and indolyl each being optionally substituted by one or more R₁ or R₂;

Y is chosen from

a bond and a C₁₋₄ saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(O)_(m) and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C₁₋₄ alkyl optionally substituted by one or more halogen atoms;

wherein when Y is the carbon chain, the left side terminal atom of Y is a carbon (the atom which is covalently attached to the heterocycle possessing W):

Z is chosen from:

aryl, heteroaryl chosen from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, furanyl, thienyl and pyranyl and heterocycle chosen from tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxo- or 2-thio-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, thiomorpholinyl sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₆ alkoxycarbonyl, aroyl, C₁₋₃acyl, oxo, pyridinyl-C₁₋₃ alkyl, imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃ alkyl, nitrile, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C₁₋₆ alkoxy or mono- or di-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m), or phenyl-S(O)_(m) wherein the phenyl ring is optionally substituted with one to two halogen, C₁₋₆ alkoxy, halogen or mono- or di-(C₁₋₃ alkyl)amino;

or Z is optionally substituted with one to three amino or amino-C₁₋₃ alkyl wherein the N atom is optionally independently mono- or di-substituted by amino C₁₋₆alkyl, C₁₋₃alkyl, arylC₀₋₃alkyl, C₁₋₅ alkoxyC₁₋₃ alkyl, C₁₋₅ alkoxy, aroyl, C₁₋₃acyl, C₁₋₃alkyl-S(O)_(m)— or arylC₀₋₃alkyl-S(O)_(m)— each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy;

or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy;

or Z is nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C₁₋₆alkyl or C₁₋₃alkoxyC₁₋₃alkyl, C₁₋₆alkyl branched or unbranched, C₁₋₆alkoxy, nitrileC₁₋₄alkyl, C₁₋₆ alkyl-S(O)_(m), aryl chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl each aryl being optionally substituted with one to three halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, di-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m) or nitrile, and phenyl-S(O)_(m), wherein the phenyl ring is optionally substituted with one to two halogen, C₁₋₆ alkoxy or mono- or di-(C₁₋₃ alkyl)amino;

R₁ and R₂ are independently chosen from:

a C₁₋₆ branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C₁₋₄ branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C₁₋₃ alkyl-S(O)_(m) optionally partially or fully halogenated, or phenylsulfonyl;

m=0, 1 or 2;

All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, “C₁₋₆alkoxy” is a C₁₋₆alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:

Ac—acetyl;

DBA—dibenzylideneacetone;

DPPF—1,1′-bis(diphenylphosphino)ferrocene;

DPPE—1,2-bis(diphenylphosphino)ethane;

DPPB—1,4-bis(diphenylphosphino)butane;

DPPP—1,3-bis(diphenylphosphino)propane;

BINAP—2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;

DME—ethylene glycol dimethylether;

DMSO—dimethyl sulfoxide;

DMF—N,N-dimethylformamide;

EtO—ethoxide;

^(i)Pr—isopropyl;

^(t)Bu—tertbutyl;

THF—tetrahydrofuran;

RT or rt—room temperature;

The term “aroyl” as used in the present specification shall be understood to mean “benzoyl” or “naphthoyl”.

The term “aryl” as used herein shall be understood to mean aromatic carbocycle, preferably phenyl and naphthyl, or heteroaryl.

The term “heterocycle”, unless otherwise noted, refers to a stable nonaromatic 4-8 membered (but preferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated. Each heterocycle consists of carbon atoms and one or more, preferably from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure. Unless otherwise stated, heterocycles include but are not limited to, for example oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl, dithianyl or 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl.

The term “heteroaryl”, unless otherwise noted, shall be understood to mean an aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ring containing 1-4 heteroatoms such as N, O and S. Unless otherwise stated, such heteroaryls include: pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl.

Terms which are analogs of the above cyclic moieties such as aryloxy or heteroaryl amine shall be understood to mean an aryl, heteroaryl, heterocycle as defined above attached to it's respective functional group.

As used herein, “nitrogen” and “sulfur” include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.

The term “halogen” as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine except as otherwise noted. The compounds made by the novel processes of the invention are only those which are contemplated to be ‘chemically stable’ as will be appreciated by those skilled in the art. For example, a compound which would have a ‘dangling valency’, or a ‘carbanion’ are not compounds made by processes contemplated by the invention.

In one embodiment of the invention there is provided a process of making the compounds of formula (A) as described hereinabove,

said process comprising:

a) synthesis of a compound of formula (C) from a compound of formula (B) via substitution with an appropriate halide X_(c). When X_(c) is Br, methods known in the art may be utilized.

When X_(c) is I, the present invention provides a novel process for the substitution of the leaving group (L) with iodide. This was achieved by using the conditions of R_(x)COCl or (R_(x)CO)₂O/metal iodide/solvent/heating (25° C.-150° C.), wherein R_(x) is chosen from —C₁₋₇ alkyl, —CF₁₋₃ and —CCl₁₋₃; the metal chosen from Na and K, and the solvent chosen from acetonitrile, acetone, DMSO, DMF and THF. Preferred conditions are AcCl and NaI in acetonitrile at 70-90° C. The leaving group L is any suitable leaving group as will be appreciated by those skilled in the art, preferably L is chosen from Cl, Br, —OCOR_(y) and —OS(O)_(m)R_(y), wherein R_(y) is aryl optionally substituted by C₁₋₄alkyl optionally halogenated, such as tolyl, or R_(y) is C₁₋₄alkyl optionally halogenated such as CF₃ and CCl₃, L is more preferably chosen from Br and Cl.

X_(a) is chosen from Br and Cl, preferably Br;

X_(c) is I or Br, preferably I;

X_(a) is attached via the 4 or 5 ring position, preferably the 5 position.

b) In a one pot process, reacting a compound of the formula (C) with a Grignard reagent R—Mg—X_(b) followed by the addition of an E—Y—Z compound wherein Y—Z is as defined above, said E—Y—Z component is further characterized as being an electrophilic derivative of Y—Z and being appropriate for Grignard reagant reactions as will be apparent to the skilled artisan, said reaction taking place in a suitable aprotic solvent at −78° C. to RT, preferably 0° C. to RT for a reaction time of ½ hour to 2 hours, preferably 1 hour, and isolating the compound of the formula (D);

 wherein:

X_(b) is chosen from Br, Cl and I;

R is aryl, C₁₋₆alkyl or C₅₋₇cycloalkyl;

As seen in Scheme V below, this one pot novel process step provides for the formation of the Grignard reagant Compound (F):

where a desirable selective formation was observed. For example the synthesis of 2-(5-halopyridyl)magnesium halides (e.g. 3 and 12) was achieved for the first time.

The process of making compounds of the formula (F) comprises:

reacting a compound of the formula (C)

 with a magnesium reagent of the formula R—MgX_(b); said reaction taking place in a suitable aprotic solvent at −78° C. to RT, for a reaction time of ½ hour to 2 hours, producing the Grignard compound of the formula (F); and wherein

X_(a), is halogen selected from Br and Cl, and X_(a) is attached via the 4 or 5 ring position;

X_(b) is halogen chosen from Br, Cl and I;

X_(c) is I or Br;

W is CR₃ or N, wherein R₃ is chosen from hydrogen, C₁₋₅alkyl, C₁₋₅alkoxy, arylC₀₋₅alkyl and —COR₄ wherein R₄ is chosen from C₁₋₅alkyl, C₁₋₅alkoxy, arylC₀₋₅alkyl and amino which is optionally independently or di-substituted by C₁₋₅alkyl, and arylC₀₋₅alkyl; W is preferably CH or N; and

R is aryl, C₁₋₆alkyl or C₅₋₇cycloalkyl.

In a preferred embodiment there is provided a process for making a compound of the formula (F) as described above and wherein

W is CH;

X_(a) is Br and attached at the 5 ring position;

X_(c) is I;

the temperature is 0° C. to RT; and

the reaction time is 1 hour.

Non-limiting examples of this reaction proceeded with complete selectivity at the 2 position in excellent yield:

In subsequent steps, the novel process of the invention further comprises:

c) reacting the compound of the formula (D) from step b) with an aryl boronic acid of the formula (E), in the presence of a catalyst chosen from nickel and palladium. Regarding the palladium (Pd) catalyst, non-limiting examples are Pd catalysts chosen from Pd(PPh₃)₂Cl₂, Pd(PPh₃)₄, PdCl₂(DPPE), PdCl₂(DPPB), PdCl₂(DPPP), PdCl₂(DPPF) and Pd/C; or the combination of a palladium source and an appropriate ligand, with the Pd source, for example, being chosen from PdCl₂, Pd(OAc)₂, Pd₂(DBA)₃, Pd(DBA)₂, and with the ligand being chosen from PPh₃, DPPF, DPPP, DPPE, DPPB, P(o-tolyl)₃, P(2,4,6-trimethoxyphenyl)₃, AsPh₃, P(^(t)Bu)₃, BINAP, and those bound to solid supports that are mimics of the aforementioned ligands, preferably PdCl₂ and PPh₃. Regarding the nickel (Ni) catalyst, examples of nickel (Ni) catalyst are those chosen from Ni(PPh₃)₂Cl₂, Ni(PPh₃)₄, NiCl₂(DPPE), NiCl₂(DPPB), NiCl₂(DPPP), NiCl₂(DPPF) and Ni/C; or the combination of a Ni source and an appropriate ligand, with the Ni source being NiCl₂, and with the ligand being chosen from PPh₃, DPPF, DPPP, DPPE, DPPB, P(o-tolyl)₃, P(2,4,6-trimethoxyphenyl)₃, AsPh₃, P(^(t)Bu)₃, BINAP, and those bound to solid supports that are mimics of the aforementioned ligands. This reaction takes place in a suitable solvent such as ethylene glycol dimethyl ether (DME), THF, toluene, methylene chloride or water, preferably DME, at 0° C. to 150° C., preferably 25° C. to 100° C., for a period of 1 to 24 hours preferably about 15 hours,

wherein P in the formula (E) is an amino protecting group such as Boc, and subsequently removing said protecting group under suitable conditions to produce a compound of the formula (A).

In a preferred embodiment of the invention there is provided a novel process of making compounds of the formula (A) as described above and wherein:

W is CH;

Ar is chosen from naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl and indolyl each being optionally substituted by one or more R₁ or R₂ groups;

Y is chosen from:

a bond and

a C₁₋₄ saturated or unsaturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N, or S(O)_(m) and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C₁₋₄ alkyl optionally substituted by one or more halogen atoms; wherein when Y is the carbon chain, the left side terminal atom of Y is a carbon (the atom which is covalently attached to the heterocycle possessing W):

Z is chosen from:

phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyranyl, pyrrolidinyl which are optionally substituted with one to three nitrile, C₁₋₃ alkyl, C₁₋₃ alkoxy, amino or mono- or di-(C₁₋₃ alkyl)amino;

tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl which are optionally substituted with one to three nitrile, C₁₋₃ alkyl, C₁₋₃ alkoxy, amino or mono- or di-(C₁₋₃ alkyl)amino;

nitrile, C₁₋₆ alkyl-S(O)_(m), halogen, C₁₋₄ alkoxy, amino, mono- or di-(C₁₋₆ alkyl)amino and di-(C₁₋₃alkyl)aminocarbonyl;

In a more preferred embodiment of the invention there is provided a novel process of making compounds of the formula (A) as described immediately above and wherein:

Ar is naphthyl;

Y is chosen from:

a bond and

a C₁₋₄ saturated carbon chain wherein the left side terminal atom of Y is a carbon (the atom which is covalently attached to the heterocycle possessing W) and one of the other carbon atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with an oxo group;

Z is chosen from:

phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl and pyrrolidinyl which are optionally substituted with one to two C₁₋₂ alkyl or C₁₋₂ alkoxy;

tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl and tetrahydropyrimidonyl which are optionally substituted with one to two C₁₋₂ alkyl or C₁₋₂ alkoxy; and

C₁₋₃ alkoxy;

In yet a more preferred embodiment of the invention there is provided a novel process of making compounds of the formula (A) as described immediately above and wherein:

Ar is 1-naphthyl wherein the NH₂ is at the 4 position;

Y is chosen from:

a bond, —CH₂—, —CH₂CH₂— and —C(O)—,;

In an ultimately preferred embodiment of the invention there is provided a novel process of making compounds of the formula (A) as described immediately above and wherein:

Y is

—CH₂—;

Z is morpholinyl;

Formation of the reaction intermediate (E) can be accomplished by first protecting an aryl-amine followed by boronic acid formation through a sequence of metal-bromine exchange, quenching with trialkylborate and hydrolysis, as can be seen in Scheme V in the conversion of 7 to 9. Compounds of the formula (E) possessing other desired Ar can be accomplished without undue experimentation by variations apparent to those of ordinary skill in the art in view of the teachings in this specification and the state of the art.

A desirable novel feature of the process of the invention is the selective formation of a 2-(5-halopyridyl) or 2-(5-halopyrimidinyl) magnesium halides, preferably 2-(5-halopyridyl) magnesium halides (e.g. 3 and 12, vide infra), and their subsequent reactions with the in situ generated E—Y—Z electrophiles. Below in Scheme 1, the addition of 2-(5-halopyridyl) magnesium halide 3 to the immonium salt 6 was carried out without the isolation of the immonium salt.

A non-limiting example for a compound of the formula (A) is the amine 1 shown in Scheme V.

Reaction intermediate (2) with a generic formula (B) above can be obtained as exemplified in Scheme VI below. Addition of a copper catalyst may be required for transformations involving certain types of electrophiles, for example the alkylation reaction of the Grignard intermediate with various alkyl halides and epoxides.

Examples of appropriate electrophiles are shown in the table below. Methods of making Y—Z electrophilic derivatives are within the skill in the art. Y component in Y—Z is a derivative of the Y of the formula (A) of the final product upon the addition of the electrophile to the Grignard intermediate. Products may be further derivatized to achieve the desired Y—Z. Such further transformations are within the skills in the art. A non-limiting example is shown below for a preferred embodiment of Z in the formula (A), i.e., the morpholino immonium salt 6. Reference in this regard may be made to Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetrahedron 1997, 53, 2941; Sliwa, H.; Blondeau, D. Heterocycles 1981, 16, 2159;.

In this example, E—Y—Z is compound 6, wherein morpholinyl represents Z and Y is —CH₂— in the final product.

As described above, any electrophile represented by Y, possessing a Z component and compatible with Grignard type reactions are contemplated to be within the scope of the invention. Additional non-limiting examples of E—Y—Z are:

Electrophiles Product (X = Br or Cl) 1. Z—CHO

wherein E—Y is an aldehyde such as Z—CHO, thus Y in Formula (A) would be —CH(OH)—. 2.

wherein NRR represent any of the above-listed Z amine moieties or heterocycles possessing a nitrogen heteroatom and Y can be alkylene such as —CH₂—, X is a countervalent anion. 3. X—(CH₂)₁₋₄—O—Z

wherein E—Y is a branched or unbranched alkoxy possessing a halogen atom X and further linked to Z, such as ClCH₂—O—Z. 4.

wherein E—Y is a C₁₋₄acyl halide such as formylchloride, NRR′ represents any of the above-listed Z amine moieties, or heterocycles possessing a nitrogen heteroatom. LG is an appropriate leaving group such as halogens. (see: Katritzky et al., J. Chem. Res. 1999, 3, 230.) 5.

wherein E—Y is a haloester moiety such as chloroformate. X is an appropriate leaving group such as halogens or alkoxy groups. (see: Satyanarayana et al., Synth. Commun. 1990, 20 (21), 3273.) 6. Z—Y—X wherein an appropriate Z—Y is substituted by halogen X, prefereably iodine, such as CH₃I. 7.

Addition of an appropriate Z attached to a reactive epoxide provides the hydroxy intermediate which is further derivatized to the desired Y component. 8.

Acylation wherein Y is an acyl attached to Z may be accomplished via the appropriate acylation reagent such as the ester shown above wherein —OR is a known leaving group. In another embodiment of the invention there is provided a process of making the compounds of formula(A): (A)

wherein Ar and W are as described above;

and wherein for the formula (A):

Y is —CH₂—; and

Z is chosen from:

heterocycle chosen from morpholinyl, thiomorpholinyl, piperidinyl and pyrrolidinyl each of the aforementioned Z are optionally substituted with one to three halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₆ alkoxycarbonyl, aroyl, C₁₋₃acyl, oxo, pyridinyl-C₁₋₃ alkyl, imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃ alkyl, nitrile, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C₁₋₆ alkoxy, di-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m), or phenyl-S(O)_(m) wherein the phenyl ring is optionally substituted with one to two halogen, C₁₋₆ alkoxy or di-(C₁₋₃ alkyl)amino;

or Z is optionally substituted with one to three one to three amino or amino-C₁₋₃ alkyl wherein the N atom is optionally independently di-substituted by aminoC₁₋₆alkyl, C₁₋₃alkyl, arylC₀₋₃alkyl, C₁₋₅ alkoxy C₁₋₃ alkyl, C₁₋₅ alkoxy, aroyl, C₁₋₃acyl, C₁₋₃alkyl-S(O)_(m)— or arylC₀₋₃alkyl-S(O)_(m)— each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy; or Z is optionally substituted with one to three aryl or heterocycle as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy;

or Z is amino wherein the N atom is optionally independently mono- or di-substituted by C₁₋₆alkyl or C₁₋₃alkoxy C₁₋₃alkyl, C₁₋₆alkyl branched or unbranched, C₁₋₆alkoxy, nitrileC₁₋₄alkyl, C₁₋₆ alkyl-S(O)_(m), aryl chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl each aryl being optionally substituted with one to three halogen, C₁₋₆ alkyl, Cl-6 alkoxy, di-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m) or nitrile, and phenyl-S(O)_(m), wherein the phenyl ring is optionally substituted with one to two halogen, C₁₋₆ alkoxy or mono- or di-(C₁₋₃ alkyl)amino;

said reaction comprising:

reacting a compound of the formula (C)

 with a magnesium reagent of the formula R—MgX_(b); said reaction taking place in a suitable aprotic solvent at −78° C. to RT, for a reaction time of ½ hour to 2 hours producing the Grignard compound (F):

wherein

X_(a), is halogen selected from Br and Cl, and X_(a) is attached to the ring via the 4 or 5 position;

X_(b) is halogen chosen from Br, Cl and I;

X_(c) is I or Br;

W is CH, CCH₃ or N; and

R is aryl, C₁₋₆alkyl or C₅₋₇cycloalkyl;

subsequently reacting the Grignard compound from the prior step with a N,N-dialkylformamide such as DMF to form an aldehyde:

 and isolating the aldehyde;

reacting the aldehyde with an appropriate Z group under nucleophilic addition conditions to provide the compound (D)

 This transformation is within the skill in the art and involves reacting of the aldehyde and the appropriate Z component under acidic conditions such as HCl, AcOH, H₂SO₄ etc, preferably AcOH, in a suitable solvent such as THF, methylene chloride, 1,2-dichloroethane, preferably 1,2-dichloroethane for 0.5-5 h (preferably 2 h) at about RT followed by in situ reduction for 0.5-5 h (preferably 2 h) to provide the product (D).

Subsequent addition of the NH₂—Ar compound can be done as described hereinabove, to provide the final product compound of the formula (A) as described above in this embodiment of the invention. A non-limiting example of this embodiment of the invention is shown in Scheme VII.

In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustrating preferred embodiments of this invention, and are not to be construed as limiting the scope of the invention in any way.

SYNTHETIC EXAMPLES Example 1 Synthesis of 5-bromo-2-iodopyridine from 2,5-dibromopyridine

2,5-Dibromopyridine (100 g) was suspended in acetonitrile (500 mL) at rt. NaI (94 g) and AcCl (45 mL) were added and the reaction was then gently refluxed for 3 h. An aliquot was analyzed by ¹H NMR and MS and the reaction was about 80% complete. The reaction was cooled to rt and quenched with a few mL of water and then K₂CO₃ aqueous solution to pH 8. EtOAc (1.5 L) was added to extract the organic materials. The organic layer was washed with saturated NaHSO₃ solution, the brine, and then dried over MgSO₄. Concentration gave crude material that was subjected to the same conditions for about 3 h at which time ¹H NMR showed that the reaction was greater than 97% complete. The same workup provided the crude material. The crude crystals were washed twice with CH₃CN and dried in the oven. The yield was 95 g.

¹H NMR (CDCl₃, 400 MHz) δ8.44 (s, 1H), 7.60 (d, J=8.26 Hz, 1H), 7.44 (d, J=8.25 Hz, 1H).

Example 2 Synthesis of 5-bromo-2-formylpyridine from 5-bromo-2-iodopyridine via the Grignard Intermediate

In a 22 L 3-neck round bottomed flask equipped with a mechanical stirrer, 1 kg (3.52 mol) of 2-iodo-5-bromopyridine was dissolved in 5 L of THF. The solution was cooled to about −15 to −10° C. 1.9 L (2 M, 380 mol, 1.08 eq) of ^(i)PrMgCl was added at a rate to keep the internal temperature below 0° C. The reaction mixture became a brown suspension. After the reaction mixture was stirred between −15 to 0° C. for 1 h, 400 mL (5.16 mol, 1.5 eq) of DMF was added at a rate to keep the internal temperature below 0° C. After stirring at this temperature for 30 min, the cooling bath was removed and the reaction was allowed to warm to room temperature over 1 h. The reaction mixture was then cooled to 0° C. and 4.0 L (7.74 mol, 2.2 eq) of 2 N HCl was added at a rate to keep the internal temperature below 25° C. The mixture was stirred for 30 min, then pH was raised from 1 to a pH 6-7 by adding about 150 mL of 2 N NaOH. The layers were separated and the THF layer was concentrated to give dark brown wet solids. The aqueous layer was extracted with 3 L of CH₂Cl₂. The CH₂Cl₂ layer was used to dissolve the residue obtained from the THF layer, the resulting solution was washed with water (2×2 L), dried by stirring with MgSO₄ (400 g) for 30 min, and filtered. Concentration of the filtrate to dryness gave 583 g of the desired aldehyde as brownish-yellow solids (89% yield after air drying).

¹H NMR (CDCl₃, 400 MHz) δ10.04 (d, J=0.68 Hz, 1H), 8.86 (t, J=0.52 Hz, 1H), 8.02 (dt, J=8.20, 0.68 Hz, 1H), 7.85 (d, J=8.48 Hz, 1H).

Example 3 Synthesis of 5-bromo-2-(4-morpholinylmethyl)pyridine from 5-bromo-2-iodopyridine via the Grignard Intermediate

To a solution of bis(l-morpholinyl)methane (130 mg) in THF (3 mL) at rt was added acetyl chloride (45 mL). The reaction was stirred for 1 h and cooled to 0° C.

In another flask, 5-bromo-2-iodopyridine (130 mg) was dissolved in THF (3 mL) at −40° C. The solution was treated with ^(i)PrMgCl (2 M in THF, 0.39 mL) at the same temperature for 15 min. Then the Grignard solution was cannulated into the immonium salt suspension generated above at 0° C. After the addition, the reaction mixture was stirred at rt for 1h and quenched with saturated NH₄Cl solution. Extraction with CH₂Cl₂, drying over MgSO₄, filtration and concentration gave a crude oil. This was further purified by column chromatography to afford the product in about 50% yield.

¹H NMR (CDCl₃, 400 MHz) δ8.60 (s, 1H), 7.76 (d, J=8.24 Hz, 1H), 7.32 (d, J=8.64 Hz, 1H), 3.72 (m, 4H), 3.59 (s, 2H), 2.48 (m, 4H).

Example 4 Synthesis of 5-bromo-2-(4-morpholinyl)methylpyridine from 5-bromo-2-formylpyridine

To a solution of 500 g (2.688 moles) aldehyde in a 5 L of 1,2- dichloroethane at room temperature was added morpholine (1.15 eq, 3.09 moles, 269 ml) in one portion. The reaction temperature went up to 29° C. After stirring the reaction mixture for 15 min, acetic acid (2.1 eq, 5.6 moles, 323 mL) was added in one portion. The temperature rose to 31° C. It was stirred for 1.5 h at room temperature. Sodium triacetoxyborohydride (1.06 eq, 2.85 moles, 604 g) was added in 100 g portions every 10 min. The temperature was maintained between 35° C. and 46° C. by gentle cooling. It was stirred for an additional 2 h.

The reaction mixture was quenched with 4 N HCl keeping the temperature below 15° C. At the end of addition, the pH of aqueous phase was between 0 and 1 (˜2200 mL). The organic phase was separated and discarded. The aqueous phase was basified with 9 N NaOH (˜740 g NaOH) to pH ˜9.5 keeping the internal temperature below 15° C. The product was extracted with methylene chloride. Evaporation of the solvent gave pure amine (660 g, 2.57 moles).

Example 5 Synthesis of 5-Bromo-3-methyl-2-pyridinecarboxaldehyde

An example of the synthesis of a compound of formula (F) in which W is CR₃ (R₃=methyl), and subsequent reaction with an electrophile is provided below and illustrated in Scheme VIII.

2,5-Dibromo-3-picoline is commercially available or may be prepared from 2-amino-5-bromo-3-methylpyridine by standard diazotization followed by bromination in Br₂/HBr. Acetyl chloride (0.68 mol, 52.7 mL) was added to a stirring solution of 2,5-dibromo-3-picoline (0.45 mol, 113 g) in acetonitrile (600 mL) followed by sodium iodide (1.66 mol, 250 g) and the reaction mixture was gently refluxed for 18 h. The cooled reaction mixture was filtered and the solid was washed with acetonitrile until colorless. It was suspended in methylene chloride and treated with aq. Na₂CO₃ until the pH was 10-11. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give a brown oil. It was subjected to iodination a second time as above (reflux time 6 h). A dark brown oil was obtained using the same work-up as above. A solution of this oil in hexane was treated with charcoal, filtered and concentrated to give a light brown oil. It slowly solidified on standing to give 5-bromo-2-iodo-3-methylpyridine as a light brown solid (95.0 g, 0.32 mol). Yield: 70%.

2-Iodo-5-bromo-3-methylpyridine (250 mg) was dissolved in THF (4.0 mL). The solution was cooled to 0° C. ^(i)PrMgCl (2 M in THF, 0.5 mL) was added at a rate to keep the internal temperature below 5° C. After the reaction mixture was stirred at 0° C. for 1 h, DMF (0.13 mL) was added at 0° C. After stirring at this temperature for 30 min, the cooling bath was removed and the reaction was allowed to warm to room temperature over 1 h. The reaction mixture was hydrolyzed by a saturated aqueous NH₄Cl solution. Then the aqueous layer was extracted with CH₂Cl₂. The CH₂Cl₂ layer was dried over MgSO₄ and concentrated to give the desired aldehyde as a brownish-yellow solid (80% yield). 

What is claimed is:
 1. A process of making the compounds of formula(A):

wherein Ar Ar is chosen from: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl and indolyl each being optionally substituted by one or more R₁ or R₂; W is CR₃ or N, wherein R₃ is chosen from hydrogen, C₁₋₅alkyl, C₁₋₅alkoxy, and arylC₀₋₅alkyl; R₁ and R₂ are independently chosen from: a C₁₋₆ branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C₁₋₄ branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C₁₋₃alkyl-S(O)_(m) optionally partially or fully halogenated or phenylsulfonyl; m=0, 1 or 2; and wherein for the formula(A): Y is —CH₂—; and Z is: heterocycle chosen from morpholinyl, thiomorpholinyl, piperidinyl and pyrrolidinyl each of the aforementioned Z are optionally substituted with one to three halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₃alkoxy-C₁₋₃alkyl, C₁₋₆alkoxycarbonyl, aroyl, C₁₋₃acyl, oxo, pyridinyl-C₁₋₃alkyl, imidazolyl-C₁₋₃alkyl, tetrahydrofuranyl-C₁₋₃alkyl, nitrile-C₁₋₃alkyl, nitrile, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C₁₋₆alkoxy, di-(C₁₋₃alkyl)amino, C₁₋₆alkyl-S(O)_(m) or phenyl-S(O)_(m) wherein the phenyl ring is optionally substituted with one to two halogen, C₁₋₆alkoxy or di-(C₁₋₃ alkyl)amino; or Z is optionally substituted with one to three one to three amino or amino-C₁₋₃alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC₁₋₆alkyl, C₁₋₃alkyl, arylC₀₋₃alkyl, C₁₋₅alkoxyC₁₋₃alkyl, C₁₋₅alkoxy, aroyl, C₁₋₃acyl, C₁₋₃alkyl-S(O)_(m)— or arylC₀₋₃alkyl-S(O)_(m)—each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C₁₋₆alkyl or C₁₋₆alkoxy; or Z is optionally substituted with one to three aryl or heterocycle as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C₁₋₆alkyl or C₁₋₆alkoxy; or Z is amino wherein the N atom is optionally independently mono- or di-substituted by C₁₋₆alkyl or C₁₋₃alkoxyC₁₋₃alkyl, C₁₋₆alkyl branched or unbranched, C₁₋₆alkoxy, nitrileC₁₋₄alkyl, C₁₋₆alkyl-S(O)_(m), aryl chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl each aryl being optionally substituted with one to three halogen, C₁₋₆alkyl, C₁₋₆alkoxy, di-(C₁₋₃alkyl)amino, C₁₋₆alkyl-S(O)_(m) or nitrile; said reaction comprising: i) reacting a compound of the formula(C)

 with a magnesium reagent of the formula R—MgX_(b); said reaction taking place in a suitable aprotic solvent at −78° C. to RT, for a reaction time of ½ hour to 2 hours producing the Grignard compound (F):

 wherein X_(a) is chosen from Br and Cl, and X_(a) is attached to the ring via the 4 or 5 position; X_(b) is chosen from Br, Cl and I; X_(c) is chosen from I and Br; wherein X_(a) and X_(c) are not the same; and R is chosen from aryl, C₁₋₆alkyl and C₅₋₇cycloalkyl; ii) subsequently reacting the Grignard compound(F) from the prior step with a N,N-dialkylformamide to form an aldehyde, and isolating the aldehyde; iii) reacting the aldehyde in step ii) with Z as defined hereinabove in this claim under acid conditions in a suitable solvent followed by in situ reduction to provide the compound(D):

 reacting the compound of the formula(D) with an aryl boronic acid of the formula (E) and a palladium catalyst, in the presence of an appropriate ligand, in a suitable solvent at 0° C. to 150° C., for about 1 to 24 hours:

 wherein the group H₃N-Ar-in the formula(A) is attached to the ring via the 4 or 5 position and wherein P in the formula(E) is an amino protecting group, and subsequently removing said protecting group under suitable conditions to produce a compound of the formula(A).
 2. The process according to claim 1 wherein W is CH or N.
 3. The process according to claim 2 wherein in step i): X_(a) is Br and attached at the 5 ring position; X_(c) is I; W is CH; R is C₁₋₆alkyl; in step ii): the N,N-dialkylformamide is DMF; the aldehyde is:

 in step iii): the acidic conditions use an acid chosen from HCl, AcOH, H₂SO₄; the solvent is chosen from THF, methylene chloride and 1,2-dichloroethane; the time is about 2 h at about RT followed by in situ reduction for about 2 h.
 4. The process according to claim 3 wherein: in step i) R is isopropyl; and in step iii) the acid is AcOH; and the solvent is 1,2-dichloroethane. 